Project Summary/Abstract This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of serious diarrheal illness. These illnesses threaten the lives of many children in poor regions of the world where sanitation and clean water are limited. While some ETEC are clearly associated with development of cholera- like diarrhea, basic molecular mechanisms underlying severe illness remain undefined. The long-term goal of these studies is to address basic questions that can inform our understanding of acute illness and more chronic sequelae that may impact or approach to development of vaccines for these organisms: ? ?Why are individuals with blood group A more susceptible to severe infections cause by ETEC ?? ? ?How does ETEC or its toxins alter intestinal surfaces to promote infection?? ? ?Are ETEC particularly well-equipped to promote these interactions?? ? ?Are there other antigens that interact with host cells to promote infections?? Studies to date have shown us that the pathogenesis of ETEC infection is actually quite complicated, potentially involving many proteins. Novel proteins that are not part of vaccines currently being tested could be added to improve the coverage and function of these vaccines. Understanding disease susceptibility on a molecular level can permit us to protect individuals at the highest risk. Addressing these fundamental questions will fill important gaps in our understanding of ETEC interactions with the intestine as well as cellular responses that develop following ETEC infections. Collectively these studies should permit a more rational approach to development of a broadly protective vaccine for these pathogens of global importance.